title: Cell surface heat shock protein 90 modulates prostate cancer cell adhesion and invasion through the integrin-β1/focal adhesion kinase/c-Src signaling pathway.
abstract: Heat shock protein (Hsp) 90 is a molecular chaperone that maintains the active conformation and function of numerous client oncoproteins in cancer cells. Hsp90 has also been detected on the plasma membrane of cells, and its expression has been suggested to correlate with metastatic potential. We studied the PC3 cell line, which is a highly invasive human prostate cancer cell line, and confirmed that Hsp90 is present on the cell surface of PC3 cells. Interestingly, cell surface Hsp90 was also specifically localized at the leading edge of migrating cells. By using a specific antibody that inhibited cell surface Hsp90, adhesion and invasion of PC3 cells were significantly suppressed in vitro. Concomitantly with these findings, we demonstrated that the inhibition of cell surface Hsp90 not only inhibited the FN-dependent association between FAK, c-Src and integrin β1, but also significantly inhibited the phosphorylation of FAK and c-Src, as well as their downstream targets paxillin and p130Cas. Additionally, the Hsp90 antibody reversed cell invasion stimulated by overexpression of FAK. These data indicate that cell surface Hsp90 is involved in prostate cancer cell invasion through the integrin β1/FAK/c-Src signaling pathway. Our study provides new insights into the mechanisms of cell surface Hsp90 in cancer invasion. These results suggest that molecular targeting of cell surface Hsp90 may therefore be a novel target for the effective treatment of metastatic prostate cancer.
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, and Department of Orthopedics, Zhongshan Hospital, Shanghai 200032, PR China.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Liu
authors.forename: Zuoqin
authors.initials: Z
authors.lastname: Yan
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.forename: Muyi
authors.initials: M
authors.lastname: Guo
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Changan
authors.initials: C
authors.lastname: Guo
mesh_terms: D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases
chemical_list: D000906:Antibodies; D005353:Fibronectins; D018841:HSP90 Heat-Shock Proteins; D019012:Integrin beta1; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human